Role of Hepatic RNA Silencing in Insulin Resistance and Obesity

肝脏 RNA 沉默在胰岛素抵抗和肥胖中的作用

• 批准号: 9331616
• 负责人: Takahisa Nakamura
• 金额: $ 35.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9331616
• 关键词: 5' -AMP-activated protein kinase; Affect; Antidiabetic Drugs; Automobile Driving; Biogenesis; Chronic; Data; Diet; Endoribonucleases; Epidemic; Event; Fatty Acids; Fatty Liver; Future; Gene Expression; Genetic Transcription; Genetic Translation; Goals; Hepatic; Hepatocyte; Human; Impairment; Insulin Resistance; Life Style; Light; Liver; Mammals; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Metformin; MicroRNAs; Mitochondria; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pathogenesis; Pathway interactions; Phosphorylation; Play; Positioning Attribute; Preventive; Process; Protein Family; Protein Kinase; Proteins; RNA Interference; RNA-Induced Silencing Complex; Regulation; Research; Respiration; Risk Factors; Role; Testing; Therapeutic; Therapeutic Effect; base; blood glucose regulation; effective therapy; endonuclease; glucose metabolism; glycemic control; improved; innovation; insight; lipid metabolism; mutant; non-alcoholic fatty liver; novel; oxidation; programs; response; stem; trend

Project Summary/Abstract Drastic changes in lifestyle and dietary trends have triggered a rapid, worldwide epidemic of chronic metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD/steatosis). The need for more effective treatments of T2D and metabolic diseases has never been more urgent. This proposal investigates the innovative hypothesis that T2D results from deregulated function of hepatic Argonaute 2 (Ago2), a main component of the RNA-induced silencing complex (RISC). Our novel preliminary data indicates hepatic Ago2 plays a central role in regulating mitochondrial function in the pathogenesis of T2D. In mammals, there are four Argonaute family proteins that play crucial roles in RNA silencing. Among them, Ago2 uniquely possesses endonuclease activity that is critical for the biogenesis of specific miRNAs and for mRNA cleavage. In the hepatic Ago2-deficient state, expressions of miRNAs, which are known to impair glucose metabolism, are selectively suppressed, whereas mRNAs enhancing mitochondrial function are increased. Intriguingly, our preliminary results identified that metformin treatment induces Ago2 functional changes associated with its endonuclease activity. These preliminary data suggest unique and pivotal roles for hepatic Ago2 in regulating glucose homeostasis, leading us to hypothesize that Ago2 regulates glucose and lipid metabolism in the liver through miRNA biogenesis and RNA silencing that affects mitochondrial function. Further, we hypothesize that increased Ago2-mediated RNA silencing contribute to hepatic steatosis and insulin resistance, and decreased Ago2 function mediates the therapeutic effect of metformin. Studies in this proposal will: (1) determine the Ago2 endonuclease activity important in T2D pathogenesis; (2) dissect Ago2 function in the therapeutic effect of metformin for improved glucose metabolism in T2D; (3) delineate Ago2-dependent mRNA silencing critical in glycemic control in T2D and in metformin's action. The goal of this application is to gain a clear mechanistic understanding of the role of the hepatic Ago2- miRNA axis in the pathogenesis and in the treatment of T2D. The long-term goal of this program is to identify novel preventive and therapeutic strategies for T2D.

项目摘要/摘要 生活方式和饮食趋势的急剧变化引发了慢性代谢的迅速，全球流行病 包括2型糖尿病（T2D）和非酒精脂肪肝病（NAFLD/Steatosis）在内的疾病。需要 T2D和代谢疾病的更有效治疗从未如此紧急。 该提案调查了以下一种创新的假设，即T2D是由放松的功能引起的 Hepatic Argonaute 2（AGO2），RNA引起的沉默复合物（RISC）的主要组成部分。我们的小说 初步数据表明肝AGO2在调节线粒体功能中起着核心作用 T2D的发病机理。在哺乳动物中，有四种Argonaute家族蛋白在RNA中扮演至关重要的角色 沉默。其中，Ago2独特拥有核酸内切酶活性，这对于生物发生至关重要 特定的miRNA和mRNA裂解。在肝AGO2缺陷状态中，miRNA的表达 已知会损害葡萄糖代谢，被选择性抑制，而mRNA增强 线粒体功能增加。有趣的是，我们的初步结果确定了二甲双胍治疗 诱导AGO2与其核酸内切酶活性相关的功能变化。这些初步数据暗示 肝AGO2在调节葡萄糖稳态中的独特和关键作用，导致我们假设 AGO2通过miRNA生物发生和RNA沉默调节肝脏中的葡萄糖和脂质代谢 影响线粒体功能。此外，我们假设升高的AGO2介导的RNA沉默增加了 肝脂肪变性和胰岛素抵抗，降低AGO2功能介导 二甲双胍。 该提案中的研究将：（1）确定在T2D中重要的AGO2核酸酶活性 发病; （2）在二甲双胍的治疗作用中解剖AGO2功能可改善葡萄糖代谢 在T2D中； （3）描述T2D和二甲双胍中血糖控制中的AGO2依赖性mRNA沉默至关重要 行动。 该应用的目的是对肝AGO2-的作用有清晰的机械理解。 在发病机理和T2D处理中的miRNA轴。该计划的长期目标是确定 T2D的新型预防和治疗策略。